Phosphine-ligated palladium sulfonate palladacycles

ABSTRACT

Described are palladium precatalysts, and methods of making and using them. The palladium precatalysts show improved stability and improved reactivity in comparison to previously-described palladium precatalysts.

RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/799,620, filed Mar. 13, 2013; which claims the benefit of priority toU.S. Provisional Patent Application Ser. No. 61/657,377, filed Jun. 8,2012.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with Government support under Grant Nos.GM046059 and GM058160 awarded by the National Institutes of Health. Thegovernment has certain rights in this invention.

BACKGROUND OF THE INVENTION

Transition metal catalyst complexes play important roles in many areasof chemistry. Catalyst complexes are recognized to be influenced by thecharacteristics of the transition metal and those of the associatedligands. For example, structural features of the ligands can influencereaction rate, regioselectivity, and stereoselectivity in reactionsinvolving the catalyst complexes. For example, in coupling reactions,electron-withdrawing ligands can be expected to slow oxidative additionto, and speed reductive elimination from, the metal center; and,conversely, electron-rich ligands can be expected to speed oxidativeaddition to, and slow reductive elimination from, the metal center.

Although phosphine-ligated Pd(0) complexes constitute the activecatalyst in many reactions, such complexes are usually difficult toprepare and extremely air-sensitive.Tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃), which wasdeveloped to serve as a stable source of Pd(0), includes coordinatingdibenzylideneacetone ligands that can significantly retard the formationof the actual active catalyst complex and/or diminish its ultimatereactivity. The use of a Pd(II) salt, such as Pd(OAc)₂, whichcircumvents problems of precatalyst instability, requires in situreduction in order to generate the active Pd(0) complex. In light of thecomplications in forming phosphine-ligated Pd(0) complexes, precatalystscaffolds constituting the source of Pd and phosphine ligand weredeveloped. See FIG. 1. These precatalysts formed the active, monoligatedPd complex under mild conditions and without the need for exogenousadditives.

However, working with known precatalysts can be problematic. Forexample, the three-step preparation of precatalyst 1 (FIG. 1) involvesthe handling of sensitive organometallic intermediates and is notamenable to large-scale production. Additionally, precatalyst 1 is proneto decomposition in solution after a few hours and is not compatiblewith bulkier ligands, such as tBuBrettPhos, RockPhos, AdBrettPhos, andMe₄tBuXPhos. See FIG. 10. Precatalyst 2, which can be preparedrelatively simply, is not widely suitable; for example, it cannot beformed with bulkier ligands, such as BrettPhos, tBuXPhos, tBuBrettPhos,RockPhos, AdBrettPhos, and Me₄tBuXPhos; additionally, it does notexhibit prolonged stability in solution.

There exists a need for a new class of air-stable, moisture-stable,solution-stable, one-component Pd precatalysts that may be activatedunder standard reaction conditions and ensures the formation of theactive complex, L₁Pd(0), with a wide range of ligands.

SUMMARY OF THE INVENTION

In certain embodiments, the invention relates to a precatalyst offormula I

wherein, independently for each occurrence,

X is a non-coordinating anion;

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo; and

L is a trialkylphosphine, triarylphosphine, dialkylarylphosphine,alkyldiarylphosphine, bis(phosphine), phosphoramide, amine, bis(amine),or N-heterocyclic carbene.

In certain embodiments, the invention relates to a precatalyst offormula II

wherein, independently for each occurrence,

X is a non-coordinating anion;

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo; and

L is a trialkylphosphine, triarylphosphine, dialkylarylphosphine,alkyldiarylphosphine, bis(phosphine), phosphoramide, amine, bis(amine),or N-heterocyclic carbene.

In certain embodiments, the invention relates to a precatalyst offormula III

wherein, independently for each occurrence,

X is a non-coordinating anion;

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo;

L is a trialkylphosphine, triarylphosphine, dialkylarylphosphine,alkyldiarylphosphine, bis(phosphine), phosphoramide, amine, bis(amine),or N-heterocyclic carbene; and

R² is alkyl, haloalkyl or aryl.

In certain embodiments, the invention relates to a precatalyst offormula VII

wherein, independently for each occurrence,

X is a non-coordinating anion;

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo;

L is a trialkylphosphine, triarylphosphine, dialkylarylphosphine,alkyldiarylphosphine, bis(phosphine), phosphoramide, amine, bis(amine),or N-heterocyclic carbene; and

R^(y) is H, alkyl, haloalkyl or aryl.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein X is selected from the groupconsisting of boron tetrafluoride, tetraarylborates (such as B(C₆F₅)₄ ⁻and (B[3,5-(CF₃)₂C₆H₃]₄)⁻), hexafluoroantimonate, phosphorustetrafluoride, phosphorus hexafluoride, alkylsulfonate,haloalkylsulfonate, arylsulfonate, perchlorate, bis(alkylsulfonyl)amide,bis(fluoroalkylsulfonyl)amide, bis(arylsulfonyl)amide,(fluoroalkylsulfonyl)(fluoroalkylcarbonyl)amide, nitrate, nitrite,sulfate, hydrogensulfate, alkyl sulfate, aryl sulfate, carbonate,bicarbonate, carboxylate, phosphate, hydrogen phosphate, dihydrogenphosphate, phosphinate, and hypochlorite.

In certain embodiments, the invention relates to a dimer of formula IX

wherein, independently for each occurrence,

X is a non-coordinating anion; and

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo.

In certain embodiments, the invention relates to a dimer of formula X

wherein, independently for each occurrence,

X is a non-coordinating anion; and

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo.

In certain embodiments, the invention relates to a dimer of formula XI

wherein, independently for each occurrence,

X is a non-coordinating anion; and

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo; and

R² is alkyl, haloalkyl or aryl.

In certain embodiments, the invention relates to a dimer of formula XV

wherein, independently for each occurrence,

X is a non-coordinating anion; and

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo; and

R^(y) is H, alkyl, haloalkyl or aryl.

In certain embodiments, the invention relates to any one of theaforementioned dimers, wherein X is selected from the group consistingof boron tetrafluoride, tetraarylborates (such as B(C₆F₅)₄ ⁻ and(B[3,5-(CF₃)₂C₆H₃]₄)⁻), hexafluoroantimonate, phosphorus tetrafluoride,phosphorus hexafluoride, alkylsulfonate, haloalkylsulfonate,arylsulfonate, perchlorate, bis(alkylsulfonyl)amide,bis(fluoroalkylsulfonyl)amide, bis(arylsulfonyl)amide,(fluoroalkylsulfonyl)(fluoroalkylcarbonyl)amide, nitrate, nitrite,sulfate, hydrogensulfate, alkyl sulfate, aryl sulfate, carbonate,bicarbonate, carboxylate, phosphate, hydrogen phosphate, dihydrogenphosphate, phosphinate, and hypochlorite.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts two known precatalysts. The stereochemistry at Pd in theprecatalysts is cis or trans.

FIG. 2 depicts a palladium sulfonate dimer of the invention. Thestereochemistry at Pd in the dimer is cis or trans.

FIG. 3 depicts a palladium sulfonate dimer of the invention. Thestereochemistry at Pd in the dimer is cis or trans.

FIG. 4 depicts a palladium sulfonate dimer of the invention. Thestereochemistry at Pd in the dimer is cis or trans.

FIG. 5 depicts a palladium sulfonate dimer of the invention. Thestereochemistry at Pd in the dimer is cis or trans.

FIG. 6 depicts a general procedure to synthesize a2-aminobiphenylpalladium mesylate precatalyst of the invention from apalladium sulfonate dimer of the invention. The stereochemistry at Pd inthe precatalyst and in the dimer is cis or trans.

FIG. 7 depicts an exemplary synthesis of a 2-aminobiphenylpalladiummesylate precatalyst from a palladium sulfonate dimer of the invention.The stereochemistry at Pd in the precatalyst and in the dimer is cis ortrans.

FIG. 8 tabulates as function of the ligand used the yields of various2-aminobiphenylpalladium mesylate precatalysts of the invention formedfrom the corresponding palladium sulfonate dimer.

FIG. 9 depicts an exemplary synthesis of a 2-aminobiphenylpalladiumtriflate precatalyst from a palladium triflate dimer of the invention.The stereochemistry at Pd in the precatalyst and in the dimer is cis ortrans.

FIG. 10 depicts various ligands that may be used to prepare theprecatalysts of the invention (tBuBrettPhos=L15; AdBrettPhos=L16;RockPhos=L17).

FIG. 11 depicts various ligands that may be used to prepare theprecatalysts of the invention.

FIG. 12 depicts two palladium sulfonate dimers of the invention. Thestereochemistry at Pd in the dimers is cis or trans.

FIG. 13 depicts an exemplary synthesis of a 2-aminobiphenylpalladiumsulfonate precatalyst from [1,1′-biphenyl]-2-amine. The stereochemistryat Pd in the precatalyst and in the dimer is cis or trans.

FIG. 14 depicts the arylation of primary amines using a precatalyst ofthe invention. Reaction conditions: aryl chloride (1 mmol), amine (1.2mmol), NaOt-Bu, (1.2 mmol), OMsBrettPhos precatalyst (0.01-0.5%),BrettPhos ligand (0.01-0.5%), dioxane (1 mL) 100° C.; ^(b)aryl iodide (1mmol), amine (1.4 mmol), NaOt-Bu, (1.4 mmol), toluene (1 mL) 100° C.;^(c)Cs₂CO₃ was used as the base; ^(d)t-BuOH was used as the solvent.Yields represent an average isolated yield based on at least two runs.

FIG. 15 depicts the arylation of secondary amines using a precatalyst ofthe invention. Reaction conditions: aryl chloride (1 mmol), amine (1.2mmol), NaOt-Bu, (1.2 mmol), THF (1 mL) 85° C.; ^(b)OMsXPhos precatalystand XPhos was used; ^(c)ArBr was used. Yields represent an averageisolated yield based on two runs.

FIG. 16 depicts Suzuki-Miyaura coupling of unstable boronic acids usinga precatalyst of the invention. Reaction conditions: aryl chloride (1mmol), boronic acid (1.5 mmol), precatalyst (2%), THF (2 mL), 0.5 MK₃PO₄ (4 mL). Yields represent an average isolated yield based on tworuns.

FIG. 17 depicts the arylation of primary amides using a precatalyst ofthe invention. Reaction conditions: aryl chloride (1 mmol), amide (1.2mmol), K₃PO₄ (1.4 mmoll), precatalyst (1 mol %), tBuOH (2 mL), 110° C.,1.5 h. Yield represents an average isolated yield based on two runs.

FIG. 18 depicts the fluorination of aryl triflates using a precatalystof the invention. Reaction conditions: aryl triflate (1 mmol), cesiumfluoride (2 mmol), toluene (5 mL) 130° C.; ^(b)cyclohexane (5 mL), 120°C. Yield represents an average isolated yield based on two runs.

FIG. 19 depicts an exemplary synthesis of a 2-aminobiphenylpalladiumhexafluorophosphate precatalyst from a dimer. The stereochemistry at Pdin the precatalyst and in the dimer is cis or trans.

FIG. 20 depicts an exemplary synthesis of a 2-aminobiphenylpalladiumtetrafluoroborate precatalyst from a dimer. The stereochemistry at Pd inthe precatalyst and in the dimer is cis or trans.

FIG. 21 depicts an exemplary synthesis of a precatalyst fromN-phenyl-[1,1′-biphenyl]-2-amine. The stereochemistry at Pd in theprecatalyst and in the dimer is cis or trans.

FIG. 22 depicts an exemplary synthesis of various precatalysts of theinvention. The stereochemistry at Pd in the precatalyst and in the dimeris cis or trans.

FIG. 23 depicts the amidation of aryl chlorides using a precatalyst ofthe invention. Reaction conditions: K₃PO₄ and 1% precatalyst, in tBuOHat 110° C.

FIG. 24 depicts the fluorination of aryl triflates using a precatalystof the invention.

FIG. 25 depicts the arylation of phenols using a precatalyst of theinvention.

FIG. 26 depicts the arylation of alcohols using a precatalyst of theinvention.

FIG. 27 depicts the trifluoromethylation of aryl triflates and an arylchloride using precatalysts of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Overview

In certain embodiments, the invention relates to a palladium sulfonateprecatalyst. In certain embodiments, the synthesis of the precatalystsmay be easily accomplished from commercially available startingmaterials. In certain embodiments, the precatalysts incorporate any of awide range of phosphine ligands. In certain embodiments, theprecatalysts are markedly stable in solution. In certain embodiments,the precatalysts are stable in solution for greater than about onemonth.

Precatalysts of the Invention

In certain embodiments, the invention relates to a precatalyst offormula I

wherein, independently for each occurrence,

X is a non-coordinating anion;

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo; and

L is a trialkylphosphine, triarylphosphine, dialkylarylphosphine,alkyldiarylphosphine, bis(phosphine), phosphoramide, amine, bis(amine),or N-heterocyclic carbene.

In certain embodiments, the invention relates to a precatalyst offormula II

wherein, independently for each occurrence,

X is a non-coordinating anion;

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo; and

L is a trialkylphosphine, triarylphosphine, dialkylarylphosphine,alkyldiarylphosphine, bis(phosphine), phosphoramide, amine, bis(amine),or N-heterocyclic carbene.

In certain embodiments, the invention relates to a precatalyst offormula III

wherein, independently for each occurrence,

X is a non-coordinating anion;

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo;

L is a trialkylphosphine, triarylphosphine, dialkylarylphosphine,alkyldiarylphosphine, bis(phosphine), phosphoramide, amine, bis(amine),or N-heterocyclic carbene; and

R² is alkyl, haloalkyl or aryl.

In certain embodiments, the invention relates to a precatalyst offormula IV

wherein, independently for each occurrence,

X is a non-coordinating anion; and

L is a trialkylphosphine, triarylphosphine, dialkylarylphosphine,alkyldiarylphosphine, bis(phosphine), phosphoramide, amine, bis(amine),or N-heterocyclic carbene.

In certain embodiments, the invention relates to a precatalyst offormula V

wherein, independently for each occurrence,

X is a non-coordinating anion; and

L is a trialkylphosphine, triarylphosphine, dialkylarylphosphine,alkyldiarylphosphine, bis(phosphine), phosphoramide, amine, bis(amine),or N-heterocyclic carbene.

In certain embodiments, the invention relates to a precatalyst offormula VI

wherein, independently for each occurrence,

X is a non-coordinating anion;

L is a trialkylphosphine, triarylphosphine, dialkylarylphosphine,alkyldiarylphosphine, bis(phosphine), phosphoramide, amine, bis(amine),or N-heterocyclic carbene; and

R² is alkyl, haloalkyl or aryl.

In certain embodiments, the invention relates to a precatalyst offormula VII

wherein, independently for each occurrence,

X is a non-coordinating anion;

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo;

L is a trialkylphosphine, triarylphosphine, dialkylarylphosphine,alkyldiarylphosphine, bis(phosphine), phosphoramide, amine, bis(amine),or N-heterocyclic carbene; and

R^(y) is H, alkyl, haloalkyl or aryl.

In certain embodiments, the invention relates to a precatalyst offormula VIII

wherein, independently for each occurrence,

X is a non-coordinating anion;

L is a trialkylphosphine, triarylphosphine, dialkylarylphosphine,alkyldiarylphosphine, bis(phosphine), phosphoramide, amine, bis(amine),or N-heterocyclic carbene; and

R^(y) is H, alkyl, haloalkyl or aryl.

In certain embodiments, the invention relates to a precatalyst of anyone of formulae I, II, III, IV, V, VI, VII, or VIII, wherein L is aligand described in U.S. Pat. No. 7,858,784, which is herebyincorporated by reference in its entirety.

In certain embodiments, the invention relates to a precatalyst of anyone of formulae I, II, III, IV, V, VI, VII, or VIII, wherein L is aligand described in U.S. Patent Application Publication No.2011/0015401, which is hereby incorporated by reference in its entirety.

In certain embodiments, the invention relates to a precatalyst of anyone of formulae I, II, III, IV, V, VI, VII, or VIII, wherein L isselected from the group consisting of

and tetramethylethylenediamine (TMEDA).

In certain embodiments, the invention relates to a precatalyst of anyone of formulae I, II, III, IV, V, VI, VII, or VIII, wherein L is

and R³ is H or alkyl.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein L is selected from the groupconsisting of PPh₃, Ph₂P—CH₃, PhP(CH₃)₂, P(o-tol)₃, PCy₃, P(tBu)₃,BINAP, dppb, dppe, dppf, dppp,

R^(x) is alkyl, aralkyl, cycloalkyl, or aryl;

X¹ is CH or N;

R³ is H or alkyl;

R⁴ is H, alkoxy, or alkyl;

R⁵ is alkyl or aryl; and

n is 1, 2, 3, or 4.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein X is selected from the groupconsisting of boron tetrafluoride, tetraarylborates (such as B(C₆F₅)₄ ⁻and (B[3,5-(CF₃)₂C₆H₃]₄)⁻), hexafluoroantimonate, phosphorustetrafluoride, phosphorus hexafluoride, alkylsulfonate,haloalkylsulfonate, arylsulfonate, perchlorate, bis(alkylsulfonyl)amide,bis(fluoroalkylsulfonyl)amide, bis(arylsulfonyl)amide,(fluoroalkylsulfonyl)(fluoroalkylcarbonyl)amide, nitrate, nitrite,sulfate, hydrogensulfate, alkyl sulfate, aryl sulfate, carbonate,bicarbonate, carboxylate, phosphate, hydrogen phosphate, dihydrogenphosphate, phosphinate, and hypochlorite.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein X is alkylsulfonate; and the alkylis substituted alkyl. In certain embodiments, the invention relates toany one of the aforementioned precatalysts, wherein X is alkylsulfonate;and the alkyl is unsubstituted alkyl.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein X is alkylsulfonate; and the alkylis methyl, ethyl, propyl, or butyl. In certain embodiments, theinvention relates to any one of the aforementioned precatalysts, whereinX is alkylsulfonate; and the alkyl is methyl or ethyl.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein X is haloalkylsulfonate. In certainembodiments, the invention relates to any one of the aforementionedprecatalysts, wherein X is fluoroalkylsulfonate.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein X is fluoromethylsulfonate. Incertain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein X is trifluoromethylsulfonate.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein X is cycloalkylalkylsulfonate. Incertain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein X is

or its enantiomer.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein X is arylsulfonate; and the aryl issubstituted aryl. In certain embodiments, the invention relates to anyone of the aforementioned precatalysts, wherein X is arylsulfonate; andthe aryl is unsubstituted aryl.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein X is phenylsulfonate. In certainembodiments, the invention relates to any one of the aforementionedprecatalysts, wherein X is methylphenylsulfonate. In certainembodiments, the invention relates to any one of the aforementionedprecatalysts, wherein X is p-toluenesulfonate.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein R¹ is H or alkyl. In certainembodiments, the invention relates to any one of the aforementionedprecatalysts, wherein R¹ is H.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein R² is substituted alkyl. In certainembodiments, the invention relates to any one of the aforementionedprecatalysts, wherein R² is unsubstituted alkyl.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein R² is methyl, ethyl, propyl, orbutyl.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein R² is substituted aryl. In certainembodiments, the invention relates to any one of the aforementionedprecatalysts, wherein R² is unsubstituted aryl.

In certain embodiments, the invention relates to any one of theaforementioned precatalysts, wherein R² is phenyl.

In certain embodiments, the invention relates to a compound selectedfrom the group consisting of:

wherein L is selected from the group consisting of PPh₃, P(o-tol)₃,PCy₃, P(tBu)₃, BINAP, dppf, dppp,

In certain embodiments, the invention relates to a compound of thefollowing structure:

wherein L is selected from the group consisting of PPh₃, P(o-tol)₃,PCy₃, P(tBu)₃, BINAP, dppf,

In certain embodiments, the invention relates to a compound of thefollowing structure:

wherein L is selected from the group consisting of

In certain embodiments, the invention relates to a compound of any oneof the following structures:

wherein

R is H, alkyl, or aryl; and

L is any one of the aforementioned ligands.

In certain embodiments, the invention relates to a compound of any oneof the following structures:

wherein

R is H, alkyl, or aryl; and

L is any one of the aforementioned ligands.

In certain embodiments, the invention relates to a compound of any oneof the following structures:

wherein

R is H, alkyl, or aryl; and

L is any one of the aforementioned ligands.

Dimers of the Invention

In certain embodiments, the invention relates to a dimer of formula IX

wherein, independently for each occurrence,

X is a non-coordinating anion; and

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo.

In certain embodiments, the invention relates to a dimer of formula X

wherein, independently for each occurrence,

X is a non-coordinating anion; and

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo.

In certain embodiments, the invention relates to a dimer of formula XI

wherein, independently for each occurrence,

X is a non-coordinating anion; and

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo; and

R² is alkyl, haloalkyl or aryl.

In certain embodiments, the invention relates to a dimer of formula XII

wherein X is a non-coordinating anion.

In certain embodiments, the invention relates to a dimer of formula XIII

wherein X is a non-coordinating anion.

In certain embodiments, the invention relates to a dimer of formula XIV

wherein

X is a non-coordinating anion; and

R² is alkyl, haloalkyl or aryl.

In certain embodiments, the invention relates to a dimer of formula XV

wherein, independently for each occurrence,

X is a non-coordinating anion; and

R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, or halo; and

R^(y) is H, alkyl, haloalkyl or aryl.

In certain embodiments, the invention relates to a dimer of formula XVI

wherein

X is a non-coordinating anion; and

R^(y) is H, alkyl, haloalkyl or aryl.

In certain embodiments, the invention relates to any one of theaforementioned dimers, wherein X is selected from the group consistingof boron tetrafluoride, tetraarylborates (such as B(C₆F₅)₄ ⁻ and(B[3,5-(CF₃)₂C₆H₃]₄)⁻), hexafluoroantimonate, phosphorus tetrafluoride,phosphorus hexafluoride, alkylsulfonate, haloalkylsulfonate,arylsulfonate, perchlorate, bis(alkylsulfonyl)amide,bis(fluoroalkylsulfonyl)amide, bis(arylsulfonyl)amide,(fluoroalkylsulfonyl)(fluoroalkylcarbonyl)amide, nitrate, nitrite,sulfate, hydrogensulfate, alkyl sulfate, aryl sulfate, carbonate,bicarbonate, carboxylate, phosphate, hydrogen phosphate, dihydrogenphosphate, phosphinate, and hypochlorite.

In certain embodiments, the invention relates to any one of theaforementioned dimers, wherein X is alkylsulfonate; and the alkyl issubstituted alkyl. In certain embodiments, the invention relates to anyone of the aforementioned dimers, wherein X is alkylsulfonate; and thealkyl is unsubstituted alkyl.

In certain embodiments, the invention relates to any one of theaforementioned dimers, wherein X is alkylsulfonate; and the alkyl ismethyl, ethyl, propyl, or butyl. In certain embodiments, the inventionrelates to any one of the aforementioned dimers, wherein X isalkylsulfonate; and the alkyl is methyl or ethyl.

In certain embodiments, the invention relates to any one of theaforementioned dimers, wherein X is haloalkylsulfonate. In certainembodiments, the invention relates to any one of the aforementioneddimers, wherein X is fluoroalkylsulfonate.

In certain embodiments, the invention relates to any one of theaforementioned dimers, wherein X is fluoromethylsulfonate. In certainembodiments, the invention relates to any one of the aforementioneddimers, wherein X is trifluoromethylsulfonate.

In certain embodiments, the invention relates to any one of theaforementioned dimers, wherein X is cycloalkylalkylsulfonate. In certainembodiments, the invention relates to any one of the aforementioneddimers, wherein X is

or its enantiomer.

In certain embodiments, the invention relates to any one of theaforementioned dimers, wherein X is arylsulfonate; and the aryl issubstituted aryl. In certain embodiments, the invention relates to anyone of the aforementioned dimers, wherein X is arylsulfonate; and thearyl is unsubstituted aryl.

In certain embodiments, the invention relates to any one of theaforementioned dimers, wherein X is phenylsulfonate. In certainembodiments, the invention relates to any one of the aforementioneddimers, wherein X is methylphenylsulfonate. In certain embodiments, theinvention relates to any one of the aforementioned dimers, wherein X isp-toluenesulfonate.

In certain embodiments, the invention relates to any one of theaforementioned dimers, wherein R¹ is H or alkyl. In certain embodiments,the invention relates to any one of the aforementioned dimers, whereinR¹ is H.

In certain embodiments, the invention relates to any one of theaforementioned dimers, wherein R² is substituted alkyl. In certainembodiments, the invention relates to any one of the aforementioneddimers, wherein R² is unsubstituted alkyl.

In certain embodiments, the invention relates to any one of theaforementioned dimers, wherein R² is methyl, ethyl, propyl, or butyl.

In certain embodiments, the invention relates to any one of theaforementioned dimers, wherein R² is substituted aryl. In certainembodiments, the invention relates to any one of the aforementioneddimers, wherein R² is unsubstituted aryl.

In certain embodiments, the invention relates to any one of theaforementioned dimers, wherein R² is phenyl.

Methods of the Invention

In certain embodiments, the invention relates to a method of Scheme 1:

wherein,

the precatalyst is any one of the aforementioned precatalysts;

L is defined as above;

Ar is aryl or heteroaryl;

q is 0, 1, 2, 3, or 4;

R⁶ is alkoxy, alkyl ester, alkylcarbonyl, hydroxyalkyl, cyano, halo,amino, cycloalkyl, aryl, haloalkyl, nitro, hydroxy, alkoxy, aryloxy, oralkyl; and

R⁷ is aryl, heteroaryl, aralkyl, heteroaralkyl, alkyl, cycloalkyl.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein temperature 1 is from about 50° C. toabout 150° C. In certain embodiments, the invention relates to any oneof the aforementioned methods, wherein temperature 1 is about 55° C.,about 60° C., about 65° C., about 70° C., about 75° C., about 80° C.,about 85° C., about 90° C., about 95° C., about 100° C., about 105° C.,about 110° C., about 115° C., about 120 C, about 125° C., about 130° C.,about 135° C., about 140° C., or about 145° C.

In certain embodiments, the invention relates to a method of Scheme 2:

wherein,

the precatalyst is any one of the aforementioned precatalysts;

L is defined as above;

Ar is aryl or heteroaryl;

q is 0, 1, 2, 3, or 4;

R⁶ is alkoxy, alkyl ester, alkylcarbonyl, hydroxyalkyl, cyano, halo,amino, cycloalkyl, aryl, haloalkyl, nitro, hydroxy, alkoxy, aryloxy, oralkyl;

R⁷ is alkyl, aralkyl, aryl, or heteroaryl; and

R⁸ is alkyl, aralkyl, aryl, or heteroaryl, or, R⁷ and R⁸, takentogether, form a cycloalkyl or heterocycloalkyl ring;

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein temperature 2 is from about 40° C. toabout 120° C. In certain embodiments, the invention relates to any oneof the aforementioned methods, wherein temperature 2 is about 45° C.,about 50° C., about 55° C., about 60° C., about 65° C., about 70° C.,about 75° C., about 80° C., about 85° C., about 90° C., about 95° C.,about 100° C., about 105° C., about 110° C., or about 115° C.

In certain embodiments, the invention relates to a method of Scheme 3:

wherein,

the precatalyst is any one of the aforementioned precatalysts;

Ar is aryl or heteroaryl;

q is 0, 1, 2, 3, or 4;

R⁶ is alkoxy, alkyl ester, alkylcarbonyl, hydroxyalkyl, cyano, halo,amino, cycloalkyl, aryl, haloalkyl, nitro, hydroxy, alkoxy, aryloxy, oralkyl; and

Ar¹ is aryl or heteroaryl.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein temperature 3 is from about 10° C. toabout 60° C. In certain embodiments, the invention relates to any one ofthe aforementioned methods, wherein temperature 3 is about 15° C., about20° C., about 25° C., about 30° C., about 35° C., about 40° C., about45° C., or about 50° C.

In certain embodiments, the invention relates to a method of Scheme 4:

wherein,

the precatalyst is any one of the aforementioned precatalysts;

q is 0, 1, 2, 3, or 4;

R⁶ is alkoxy, alkyl ester, alkylcarbonyl, hydroxyalkyl, cyano, halo,amino, cycloalkyl, aryl, haloalkyl, nitro, hydroxy, alkoxy, aryloxy, oralkyl; and

R⁹ is aralkyl, heteroaralkyl, aryl, heteroaryl, or cycloalkyl.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein temperature 4 is from about 60° C. toabout 160° C. In certain embodiments, the invention relates to any oneof the aforementioned methods, wherein temperature 4 is about 65° C.,about 70° C., about 75° C., about 80° C., about 85° C., about 90° C.,about 95° C., about 100° C., about 105° C., about 110° C., about 115°C., about 120 C, about 125° C., about 130° C., about 135° C., about 140°C., about 145° C., about 150° C., or about 155° C.

In certain embodiments, the invention relates to a method of Scheme 5:

wherein,

the precatalyst is any one of the aforementioned precatalysts;

q is 0, 1, 2, 3, or 4; and

R⁶ is alkoxy, alkyl ester, alkylcarbonyl, hydroxyalkyl, cyano, halo,amino, cycloalkyl, aryl, haloalkyl, nitro, hydroxy, alkoxy, aryloxy, oralkyl.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein temperature 5 is from about 70° C. toabout 190° C. In certain embodiments, the invention relates to any oneof the aforementioned methods, wherein temperature 5 is about 75° C.,about 80° C., about 85° C., about 90° C., about 95° C., about 100° C.,about 105° C., about 110° C., about 115° C., about 120 C, about 125° C.,about 130° C., about 135° C., about 140° C., about 145° C., about 150°C., about 155° C., about 160° C., about 165° C., about 170° C., about175° C., or about 180° C.

In certain embodiments, the invention relates to a method of Scheme 8:

wherein, independently for each occurrence,

the precatalyst is any one of the aforementioned precatalysts;

X² is halo;

Ar¹ is aryl or heteroaryl;

Ar² is aryl or heteroaryl, which is optionally substituted with 1, 2, 3,or 4 R¹¹;

q is 0, 1, 2, 3, or 4;

R⁶ is alkoxy, alkyl ester, alkylcarbonyl, hydroxyalkyl, cyano, halo,amino, cycloalkyl, aryl, haloalkyl, nitro, hydroxy, alkoxy, aryloxy, oralkyl; and

R¹¹ is alkoxy, alkyl ester, alkylcarbonyl, hydroxyalkyl, cyano, halo,amino, cycloalkyl, aryl, haloalkyl, nitro, hydroxy, alkoxy, aryloxy,alkyl, alkylthio, or cyanoalkyl.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein temperature 8 is from about 10° C. toabout 90° C. In certain embodiments, the invention relates to any one ofthe aforementioned methods, wherein temperature 8 is about 10° C., about15° C., about 20° C., about 25° C., about 30° C., about 35° C., about40° C., about 45° C., about 50° C., about 55° C., about 60° C., about65° C., about 70° C., about 75° C., about 80° C., about 85° C., or about90° C.

In certain embodiments, the invention relates to a method of Scheme 9:

wherein, independently for each occurrence,

the precatalyst is any one of the aforementioned precatalysts;

X² is halo;

Ar¹ is aryl or heteroaryl;

q is 0, 1, 2, 3, or 4;

R⁶ is alkoxy, alkyl ester, alkylcarbonyl, hydroxyalkyl, cyano, halo,amino, cycloalkyl, aryl, haloalkyl, nitro, hydroxy, alkoxy, aryloxy, oralkyl; and

R¹² is alkyl or substituted alkyl (including but not limited to aralkyl,fluoroalkylalkyl, or cycloalkylalkyl).

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein temperature 9 is from about 50° C. toabout 160° C. In certain embodiments, the invention relates to any oneof the aforementioned methods, wherein temperature 9 is about 50° C.,about 55° C., about 60° C., about 65° C., about 70° C., about 75° C.,about 80° C., about 85° C., about 90° C., about 95° C., about 100° C.,about 105° C., about 110° C., about 115° C., about 120 C, about 125° C.,about 130° C., about 135° C., about 140° C., about 145° C., about 150°C., about 155° C., or about 160° C.

In certain embodiments, the invention relates to a method of Scheme 10:

wherein, independently for each occurrence,

the precatalyst is any one of the aforementioned precatalysts;

X³ is halo, triflate, or mesylate;

Ar¹ is aryl or heteroaryl;

q is 0, 1, 2, 3, or 4; and

R⁶ is alkoxy, alkyl ester, alkylcarbonyl, hydroxyalkyl, cyano, halo,amino, cycloalkyl, aryl, haloalkyl, nitro, hydroxy, alkoxy, aryloxy, oralkyl.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein temperature 10 is from about 50° C. toabout 160° C. In certain embodiments, the invention relates to any oneof the aforementioned methods, wherein temperature 10 is about 50° C.,about 55° C., about 60° C., about 65° C., about 70° C., about 75° C.,about 80° C., about 85° C., about 90° C., about 95° C., about 100° C.,about 105° C., about 110° C., about 115° C., about 120 C, about 125° C.,about 130° C., about 135° C., about 140° C., about 145° C., about 150°C., about 155° C., or about 160° C.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein base 1, base 2, base 3, base 4, base 8,or base 9 comprises t-butoxy, carbonate, or phosphate.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein base 1, base 2, base 3, base 4, base 8,or base 9 is NaOt-Bu, Cs₂CO₃, K₂CO₃, or K₃PO₄.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein solvent 1, solvent 2, solvent 3, orsolvent 4 is a non-polar solvent or a polar aprotic solvent.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein solvent 1, solvent 2, solvent 3, orsolvent 4 is an ether or an alcohol.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein solvent 1, solvent 2, solvent 3, orsolvent 4 comprises dioxane, tetrahydrofuran, water, or tBuOH.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein solvent 5 or solvent 9 is a non-polarsolvent.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein solvent 5 or solvent 9 comprisestoluene.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein solvent 8 is a non-polar solvent.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein solvent 8 comprises toluene. In certainembodiments, the invention relates to any one of the aforementionedmethods, wherein solvent 8 comprises toluene and dimethoxyether.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein solvent 10 comprises dioxane andtoluene. In certain embodiments, the invention relates to any one of theaforementioned methods, wherein solvent 10 comprises dioxane and toluenein a 1:1 ratio.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein the precatalyst is present in an amountfrom about 0.005 mol % to about 10 mol %.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein the precatalyst is present in about0.005 mol %, about 0.01 mol %, about 0.05 mol %, about 0.1 mol %, about0.5 mol %, about 1 mol %, about 2 mol %, about 3 mol %, about 4 mol %,or about 5 mol %.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein L is present in an amount from about0.005 mol % to about 10 mol %.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein L is present in about 0.005 mol %, about0.01 mol %, about 0.05 mol %, about 0.1 mol %, about 0.5 mol %, about 1mol %, about 2 mol %, about 3 mol %, about 4 mol %, or about 5 mol %.

In certain embodiments, the invention relates to a method of making anyone of the aforementioned dimers, according to Scheme 6a

wherein X is a non-coordinating anion.

In certain embodiments, the invention relates to a method of making anyone of the aforementioned dimers, according to Scheme 6b

wherein X is a non-coordinating anion.

In certain embodiments, the invention relates to a method of making anyone of the aforementioned dimers, according to Scheme 6c

wherein X is a non-coordinating anion.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein the Pd(II) source is Pd(OAc)₂.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein the solvent is a non-polar solvent or apolar aprotic solvent. In certain embodiments, the invention relates toany one of the aforementioned methods, wherein the solvent is toluene.In certain embodiments, the invention relates to any one of theaforementioned methods, wherein the solvent is THF.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein the reaction takes place at from about25° C. to about 75° C. In certain embodiments, the invention relates toany one of the aforementioned methods, wherein the reaction takes placeat about 25° C., about 30° C., about 35° C., about 40° C., about 45° C.,about 50° C., about 55° C., about 60° C., about 65° C., about 70° C., orabout 75° C.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein the reaction is substantially completeafter about 30 min, about 35 min, about 40 min, about 45 min, about 50min, about 55 min, or about 60 min.

In certain embodiments, the invention relates to a method of making anyone of the aforementioned precatalysts, according to Scheme 7

wherein

X is a non-coordinating anion; and

L is a ligand as defined above.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein the solvent is a polar aprotic solvent.In certain embodiments, the invention relates to any one of theaforementioned methods, wherein the solvent is THF or CH₂Cl₂.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein the reaction takes place at from about10° C. to about 40° C. In certain embodiments, the invention relates toany one of the aforementioned methods, wherein the reaction takes placeat about 15° C., about 20° C., about 25° C., about 30° C., or about 35°C.

In certain embodiments, the invention relates to any one of theaforementioned methods, wherein the reaction is substantially completeafter about 10 min, about 15 min, about 20 min, about 25 min, about 30min, about 35 min, about 40 min, about 45 min, about 50 min, about 55min, about 60 min, about 65 min, about 70 min, about 75 min, about 80min, about 85 min, or about 90 min. In certain embodiments, theinvention relates to any one of the aforementioned methods, wherein thereaction is substantially complete after about 2 h, about 3 h, about 4h, about 5 h, about 6 h, about 7 h, about 8 h, about 9 h, about 10 h,about 11 h, or about 12 h.

The reactions of the present invention may be performed under a widerange of conditions, though it will be understood that the solvents andtemperature ranges recited herein are not limitative and only correspondto exemplary modes of the processes of the invention.

In general, it will be desirable that reactions are run using mildconditions which will not adversely affect the reactants, theprecatalyst, or the product. For example, the reaction temperatureinfluences the speed of the reaction, as well as the stability of thereactants and catalyst. The reactions will usually be run attemperatures in the range of 25° C. to 300° C., more preferably in therange 25° C. to 150° C.

In general, the subject reactions are carried out in a liquid reactionmedium. The reactions may be run without addition of solvent.Alternatively, the reactions may be run in an inert solvent, preferablyone in which the reaction ingredients, including the catalyst, aresubstantially soluble. Suitable solvents include ethers such as diethylether, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether,tetrahydrofuran, water and the like; halogenated solvents such aschloroform, dichloromethane, dichloroethane, chlorobenzene, and thelike; aliphatic or aromatic hydrocarbon solvents such as benzene,xylene, toluene, hexane, pentane and the like; esters and ketones suchas ethyl acetate, acetone, and 2-butanone; polar aprotic solvents, suchas acetonitrile, dimethylsulfoxide, dimethylformamide and the like; orcombinations of two or more solvents.

The invention also contemplates reaction in a biphasic mixture ofsolvents, in an emulsion or suspension, or reaction in a lipid vesicleor bilayer. In certain embodiments, it may be preferred to perform thecatalyzed reactions in the solid phase with one of the reactants or aligand anchored to a solid support.

In certain embodiments it is preferable to perform the reactions underan inert atmosphere of a gas such as nitrogen or argon.

The reaction processes of the present invention can be conducted incontinuous, semi-continuous or batch fashion and may involve a liquidrecycle operation as desired. The processes of this invention arepreferably conducted in batch fashion. Likewise, the manner or order ofaddition of the reaction ingredients, precatalyst and solvent are alsonot generally critical to the success of the reaction, and may beaccomplished in any conventional fashion. In an order of events that, insome cases, can lead to an enhancement of the reaction rate, the base,e.g., t-BuONa, is the last ingredient to be added to the reactionmixture.

The reaction can be conducted in a single reaction zone or in aplurality of reaction zones, in series or in parallel or it may beconducted batchwise or continuously in an elongated tubular zone orseries of such zones. The materials of construction employed should beinert to the starting materials during the reaction and the fabricationof the equipment should be able to withstand the reaction temperaturesand pressures. Means to introduce and/or adjust the quantity of startingmaterials or ingredients introduced batchwise or continuously into thereaction zone during the course of the reaction can be convenientlyutilized in the processes especially to maintain the desired molar ratioof the starting materials. The reaction steps may be effected by theincremental addition of one of the starting materials to the other.Also, the reaction steps can be combined by the joint addition of thestarting materials to the metal catalyst. When complete conversion isnot desired or not obtainable, the starting materials can be separatedfrom the product and then recycled back into the reaction zone.

The processes may be conducted in either glass-lined, stainless steel orsimilar type reaction equipment. The reaction zone may be fitted withone or more internal and/or external heat exchanger(s) in order tocontrol undue temperature fluctuations, or to prevent any possible“runaway” reaction temperatures.

Furthermore, one or more of the reactants can be immobilized orincorporated into a polymer or other insoluble matrix by, for example,derivativation with one or more of substituents of the aryl group.

DEFINITIONS

For convenience, before further description of the present invention,certain terms employed in the specification, examples, and appendedclaims are collected here.

The term “alkyl” refers to the radical of saturated aliphatic groups,including straight-chain alkyl groups, branched-chain alkyl groups,cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, andcycloalkyl substituted alkyl groups. In preferred embodiments, astraight chain or branched chain alkyl has 30 or fewer carbon atoms inits backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ for branchedchain), and more preferably 20 or fewer. Likewise, preferred cycloalkylshave from 3-10 carbon atoms in their ring structure, and more preferablyhave 5, 6 or 7 carbons in the ring structure.

The term “aralkyl”, as used herein, refers to an alkyl group substitutedwith an aryl group (e.g., an aromatic or heteroaromatic group).

Unless the number of carbons is otherwise specified, “lower alkyl” asused herein means an alkyl group, as defined above, but having from oneto ten carbons, more preferably from one to six carbon atoms in itsbackbone structure. Likewise, “lower alkenyl” and “lower alkynyl” havesimilar chain lengths but with at least two carbon atoms. Preferredalkyl groups are lower alkyls. In preferred embodiments, a substituentdesignated herein as alkyl is a lower alkyl.

The term “aryl” as used herein includes 5-, 6- and 7-membered aromaticgroups that may include from zero to four heteroatoms, for example,benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene,imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine,pyridazine and pyrimidine, and the like. Those aryl groups havingheteroatoms in the ring structure may also be referred to as “arylheterocycles” or “heteroaromatics”. The aromatic ring can be substitutedat one or more ring positions with such substituents as described above,for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido,phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromaticor heteroaromatic moieties, —CF₃, —CN, or the like. The term “aryl” alsoincludes polycyclic ring systems having two or more cyclic rings inwhich two or more carbons are common to two adjoining rings (the ringsare “fused rings”) wherein at least one of the rings is aromatic, e.g.,the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls,aryls and/or heterocyclyls.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms, and dba represent methyl,ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl, methanesulfonyl, and dibenzylideneacetone,respectively. Also, “DCM” stands for dichloromethane; “rt” stands forroom temperature, and may mean about 20° C., about 21° C., about 22° C.,about 23° C., about 24° C., about 25° C., or about 26° C.; “THF” standsfor tetrahydrofuran; “BINAP” stands for2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; “dppf” stands for1,1′-bis(diphenylphosphino)ferrocene; “dppb” stands for1,4-bis(diphenylphosphinobutane; “dppp” stands for1,3-bis(diphenylphosphino)propane; “dppe” stands for1,2-bis(diphenylphosphino)ethane. A more comprehensive list of theabbreviations utilized by organic chemists of ordinary skill in the artappears in the first issue of each volume of the Journal of OrganicChemistry; this list is typically presented in a table entitled StandardList of Abbreviations. The abbreviations contained in said list, and allabbreviations utilized by organic chemists of ordinary skill in the artare hereby incorporated by reference.

The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstitutedbenzenes, respectively. For example, the names 1,2-dimethylbenzene andortho-dimethylbenzene are synonymous.

The terms “heterocyclyl” or “heterocyclic group” refer to 3- to10-membered ring structures, more preferably 3- to 7-membered rings,whose ring structures include one to four heteroatoms. Heterocycles canalso be polycycles. Heterocyclyl groups include, for example, thiophene,thianthrene, furan, pyran, isobenzofuran, chromene, xanthene,phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole,pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole,indole, indazole, purine, quinolizine, isoquinoline, quinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine,phenanthroline, phenazine, phenarsazine, phenothiazine, furazan,phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine,piperazine, morpholine, lactones, lactams such as azetidinones andpyrrolidinones, sultams, sultones, and the like. The heterocyclic ringcan be substituted at one or more positions with such substituents asdescribed above, as for example, halogen, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido,phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic orheteroaromatic moiety, —CF₃, —CN, or the like.

The term “non-coordinating anion” relates to a negatively charged moietythat interacts weakly with cations. Non-coordinating anions are usefulin studying the reactivity of electrophilic cations, and are commonlyfound as counterions for cationic metal complexes with an unsaturatedcoordination sphere. In many cases, non-coordinating anions have anegative charge that is distributed symmetrically over a number ofelectronegative atoms. Salts of these anions are often soluble non-polarorganic solvents, such as dichloromethane, toluene, or alkanes.

The terms “polycyclyl” or “polycyclic group” refer to two or more rings(e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/orheterocyclyls) in which two or more carbons are common to two adjoiningrings, e.g., the rings are “fused rings”. Rings that are joined throughnon-adjacent atoms are termed “bridged” rings. Each of the rings of thepolycycle can be substituted with such substituents as described above,as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromaticmoiety, —CF₃, —CN, or the like.

The term “heteroatom” as used herein means an atom of any element otherthan carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen,sulfur and phosphorous.

As used herein, the term “nitro” means —NO₂; the term “halogen”designates —F, —Cl, —Br or —I; the term “sulfhydryl” means —SH; the term“hydroxyl” means —OH; and the term “sulfonyl” means —SO₂—.

The terms “amine” and “amino” are art recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that can berepresented by the general formula:

wherein R₉, R₁₀ and R′₁₀ each independently represent a hydrogen, analkyl, an alkenyl, —(CH₂)_(m)—R₈, or R₉ and R₁₀ taken together with theN atom to which they are attached complete a heterocycle having from 4to 8 atoms in the ring structure; R₈ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle or a polycycle; and m is zero or an integerin the range of 1 to 8. In preferred embodiments, only one of R₉ or R₁₀can be a carbonyl, e.g., R₉, R₁₀ and the nitrogen together do not forman imide. In even more preferred embodiments, R₉ and R₁₀ (and optionallyR′₁₀) each independently represent a hydrogen, an alkyl, an alkenyl, or—(CH₂)_(m)—R₈. Thus, the term “alkylamine” as used herein means an aminegroup, as defined above, having a substituted or unsubstituted alkylattached thereto, i.e., at least one of R₉ and R₁₀ is an alkyl group.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized andrefer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl,and nonafluorobutanesulfonyl groups, respectively. The terms triflate,tosylate, mesylate, and nonaflate are art-recognized and refer totrifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain said groups, respectively.

The phrase “protecting group” as used herein means temporarymodifications of a potentially reactive functional group which protectit from undesired chemical transformations. Examples of such protectinggroups include esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991).

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described hereinabove. The permissible substituentscan be one or more and the same or different for appropriate organiccompounds. For purposes of this invention, the heteroatoms, such asnitrogen, may have hydrogen substituents and/or any permissiblesubstituents of organic compounds described herein which satisfy thevalencies of the heteroatoms.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

EXEMPLIFICATION

The invention may be understood with reference to the followingexamples, which are presented for illustrative purposes only and whichare non-limiting. The substrates utilized in these examples were eithercommercially available, or were prepared from commercially availablereagents.

Example 1 Synthesis of Palladium Sulfonate Dimers

2-Aminobiphenylpalladium Mesylate Dimer:

A 300-mL round-bottomed flask equipped with a magnetic stir bar andfitted with a rubber septum was charged with 2-ammoniumbiphenyl mesylate(7.89 g, 30.0 mmol, 1.00 eq) and palladium acetate (6.72 g, 30.0 mmol,1.00 eq). The flask was evacuated and backfilled with argon (thissequence was repeated three times), after which 120 mL anhydrous toluenewas added. The mixture was stirred at 50° C. for 45 min or until itbecame milky and off-white in appearance. After cooling to roomtemperature the suspension was filtered, washed with toluene (25 mL) anddiethyl ether (3×25 mL), and dried under vacuum for 24 hours to affordthe title compound as an off-white to tan solid. Yield: 10.2 g (92%).FIG. 2.

2-Aminobiphenylpalladium Ethanesulfonate Dimer

A 50-mL round-bottomed flask equipped with a magnetic stir bar andfitted with a rubber septum was charged with 2-ammoniumbiphenylethanesulfonate (1.20 g, 4.30 mmol, 1.00 eq.) and palladium acetate (963mg, 4.30 mmol, 1.00 eq). Then toluene (25 mL) was added by syringe andthe mixture was heated at 50° C. for 45 minutes or it became a milky,off-white suspension. After cooling to room temperature the suspensionwas filtered and washed with diethyl ether (3×10 mL) and dried undervacuum to afford the title compound as a deep beige solid. Yield: 1.61g, 98%. FIG. 3.

2-Aminobiphenylpalladium Camphorsulfonate Dimer

A 50-mL round-bottomed flask equipped with a magnetic stir bar andbitted with a rubber septum was charged with 2-aminobiphenyl (338 mg,2.00 mmol, 1.00 eq), (±)-10-camphorsulfonic acid (464 mg, 2.00 mmol,1.00 eq.) and palladium acetate (448 mg, 2.00 mmol, 1.00 eq). Thentoluene (20 mL) was added by syringe and the mixture was stirred at 50°C. for 45 minutes or until milky and off-white in appearance. Aftercooling to room temperature the suspension was filtered and washed withdiethyl ether (3×10 mL) and dried under vacuum to afford the titlecompound as a tan solid. Yield: 677 mg, 67%. FIG. 4.

2-Aminobiphenylpalladium Tosylate Dimer

A 24-mL test tube equipped with a magnetic stir bar and fitted with ateflon septum was charged with 2-aminobiphenyl (169 mg, 1.00 mmol, 1.00eq) and p-toluenesulfonic acid monohydrate (192 mg, 1.00 mmol, 1.00 eq).The tube was sealed and then evacuated and backfilled with argon,followed by the addition of THF (5 mL). The resulting suspension wasstirred at room temperature for 10 minutes, after which palladiumacetate (224 mg, 1.00 mmol, 1.00 eq) was added and rinsed down the wallsof the flask with the use of additional THF (2 mL). The mixture was thenheated at 50° C. for 30 min, or until it became a homogenous yellowsolution. After cooling to room temperature, the solution volume wasreduced by 75% with the aid of a rotary evaporator, after which theproduct was precipitated with hexanes. The resulting solid was filteredand dried under vacuum for 24 hours to afford the title compound as abeige solid. Yield: 355 mg, 80%. FIG. 5.

Example 2 Synthesis of 2-Aminobiphenylpalladium Mesylate Precatalysts

2-Aminobiphenylpalladium Mesylate Precatalyst General Procedure:

A test tube, equipped with a magnetic stir bar and fitted with a Teflonscrew-cap, was charged with 2-aminobiphenylpalladium mesylate dimer (370mg, 0.50 mmol, 0.50 eq) and ligand (1.00 mmol, 1.00 eq). THF or DCM (5mL) was added by syringe and the reaction was stirred for 15 min to 1 h.The reaction progress was monitored by ³¹P NMR, observing thedisappearance of free ligand signal and appearance of the precatalystsignal downfield. After completion, the reaction mixture was transferredto a scintillation vial and the solvent was removed under vacuum at roomtemperature until ˜10% remained. The residue was then triturated withpentane. The resulting solid was isolated via filtration and furtherdried under vacuum. FIG. 6.

2-Aminobiphenylpalladium Mesylate XPhos Precatalyst (RepresentativeProcedure)

A 300-mL round-bottomed flask equipped with a stir bar and rubber septumwas charged with μ-OMs dimer 3 (11.92 g, 15.25 mmol, 0.50 eq) and XPhos(14.52 g, 30.5 mmol, 1.00 eq). The flask was evacuated under vacuum andbackfilled with argon (this procedure was repeated twice), after whichTHF (120 mL) was added. The reaction mixture was stirred at roomtemperature for 45 min. After removal of 90% of the solvent under vacuumthe product was precipitated from pentane to afford the title compoundas an off-white solid as the 1:1 THF complex. THF could be removed bydissolving the solid in DCM and reprecipitating with pentane. Yield:25.5 g, 92%. FIG. 7.

FIG. 8 tabulates the % yield of various precatalysts formed using theprocedures outlined above.

Example 3 Synthesis of 2-Aminobiphenylpalladium Triflate Precatalysts

2-Aminobiphenylpalladium Triflate tBuBrettPhos Precatalyst:

A 250-mL round-bottomed flask equipped with a stirbar was charged with2-aminobiphenylpalladium chloride dimer (3.41 g, 5.5 mmol, 0.50 eq) andsilver triflate (2.82 g, 11 mmol, 1.00 eq.) and shielded from light.Then dichloromethane (100 mL) was added and the mixture was stirred atroom temperature for 30 min. The suspension was then filtered through awet pad of Celite into a 500-mL round-bottomed flask equipped with astir bar containing tBuBrettPhos (5.33 g, 11 mmol, 1.00 eq). Anadditional portion of dichloromethane (50 mL) was used to rinse thefirst flask and elute the mixture through the Celite plug. The resultingmixture was stirred at room temperature for 2 h, until becoming deep redin color. After removing ˜90% of the solvent via rotary evaporation,pentane (200 mL) was added to precipitate the precatalyst. Thesuspension was sonicated for 30 minutes, crushed with a spatula andfiltered. The resulting solid was dried under vacuum overnight to givethe title compound as a dark orange solid. Yield: 9.59 g, 96%. FIG. 9.

Example 4 General Procedure for Catalyzed Arylation of Primary Amines

An oven-dried, resealable tube equipped with a magnetic stir bar andTeflon septum was charged with OMsBrettPhos precatalyst (0.01-0.5 mol%), BrettPhos (0.01-0.5 mol %) NaOt-Bu (115 mg, 1.20 mmol, 1.20 eq),aryl halide (1.00 mmol, 1.00 eq) and amine (1.20 mmol, 1.20 eq) if theyare solids. The tube was evacuated and backfilled with argon. Thisprocess was repeated three times. Then the aryl halide and amine wereadded if they are liquid, followed by dioxane (1 mL). The reaction washeated at 100° C. and monitored by thin-layer chromatography or gaschromatography, observing the disappearance of aryl halide. Aftercompletion the reaction was cooled to room temperature, diluted withethyl acetate, and filtered through a plug of Celite. The solvent wasremoved via rotary evaporation and the crude product was then purifiedby flash chromatography. See FIG. 14.

Example 5 General Procedure for Catalyzed Arylation of Secondary Amines

An oven-dried resealable tube equipped with a stir bar and Teflon septumwas charged with OMsRuPhos precatalyst (0.01-1 mol %), RuPhos (0.01-1mol %) NaOtBu (115 mg, 1.20 mmol, 1.20 eq), aryl halide (1.00 mmol) andamine (1.20 mmol, 1.20 eq) if they are solids. The tube was evacuatedand backfilled with argon. This was repeated three times. Then the arylhalide and amine are added if they are liquid followed by THF (1 mL).The reaction was heated at 85° C. and monitored by thin-layerchromatography or gas chromatography, observing the disappearance ofaryl halide. After completion the reaction was cooled to roomtemperature, diluted with ethyl acetate, and filtered through a plug ofCelite. The solvent was removed via rotary evaporation and the crudeproduct was then purified by flash chromatography. See FIG. 15.

Example 6 General Procedure for Suzuki-Miyaura Coupling of UnstableBoronic Acids

A resealable tube equipped with a magnetic stir bar and Teflon septumwas charged with OMsXPhos precatalyst (2 mol %), the aryl halide (1mmol) (if a solid), and the boronic acid (1.5 mmol). The tube was thenevacuated and backfilled with argon. This process was repeated threetimes. Then the aryl halide (if a liquid) was added followed by THF (2mL) and degassed 0.5 M K₃PO₄ solution (4 mL). The reaction was thenstirred at rt or 40° for 30 min. The reaction mixture was diluted withwater (10 mL) and ethyl acetate (10 mL) and the layers are separated.The aqueous layer was extracted with ethyl acetate three times. Thecombined organic phases are dried over magnesium sulfate, concentratedunder vacuum and purified via column chromatography. See FIG. 16

Example 7 General Procedure for Arylation of Primary Amides

An oven-dried, resealable tube equipped with a magnetic stir bar andTeflon septum was charged with OTf-tBuBrettPhos precatalyst (9.1 mg, 1mol %), K₃PO₄ (297 mg, 1.40 mmol, 1.40 eq), aryl halide (1.00 mmol, 1.00eq) and amide (1.20 mmol, 1.20 eq) if they are solids. The tube wassealed and evacuated and backfilled with argon. This process wasrepeated three times. Then the aryl halide and amide were added if theyare liquids, followed by tBuOH (2 mL). The reaction was heated at 110°C. and monitored by thin-layer chromatography or gas chromatography,observing the disappearance of aryl halide. After completion, thereaction was cooled to room temperature and diluted with ethyl acetateand water. The phases were separated and the aqueous phase was backextracted with ethyl acetate (2×5 mL). The combined organic phases weredried over sodium sulfate, concentrated via rotary evaporation and thecrude product was purified by column chromatography. See FIG. 17.

Example 8 General Procedure for Fluorination of Aryl Triflates

In a nitrogen filled glovebox an oven-dried resealable tube equippedwith a stir bar was charged with (in this order) CsF (2.0 mmol, 2.0eq.), OTf-tBuBrettPhos precatalyst (1-5%), aryl triflate (1.0 mmol, 1.0eq.), and toluene (5 mL). The tube was sealed with a Teflon septum andremoved from the glovebox, and the reaction mixture was stirred at120-130° C. overnight. The reaction mixture was then allowed to cool toroom temperature, filtered through celite eluting with Et₂O, andconcentrated via rotary evaporation. The crude product was purified byflash chromatography. See FIG. 18.

Example 9 Synthesis of 2-Aminobiphenylpalladium HexafluorophosphatePrecatalysts

A test tube, equipped with a magnetic stir bar and fitted with a Teflonscrew-cap, was charged with μ-Cl dimer (78 mg, 0.125 mmol, 0.50 eq) andKPF₆ (276 mg, 1.50 mmol, 3.00 eq). The tube was sealed and evacuated andbackfilled with argon (this was repeated two times), after whichacetonitrile (3 mL) and methanol (1 mL) was added. After stirring for 30min, XPhos (238 mg, 0.50 mmol, 1.00 eq) was added and rinsed down thesides of the tube with additional acetonitrile and the mixture wasstirred overnight. After completion, the reaction mixture was elutedthrough celite and the solvent was removed via rotary evaporation. Theresidue was then triturated with pentane. The resulting solid wasisolated via filtration and further dried under vacuum. See FIG. 19.

Example 10 Synthesis of 2-Aminobiphenylpalladium TetrafluoroboratePrecatalysts

A test tube, equipped with a magnetic stir bar and fitted with a Teflonscrew-cap, was charged with μ-Cl dimer (78 mg, 0.125 mmol, 0.50 eq) andNaBF₄ (165 mg, 1.50 mmol, 3.00 eq). The tube was sealed and evacuatedand backfilled with argon (this was repeated two times), after whichacetonitrile (3 mL) and methanol (1 mL) was added. After stirring for 30min, XPhos (238 mg, 0.50 mmol, 1.00 eq) was added and rinsed down thesides of the tube with additional acetonitrile and the mixture wasstirred overnight. After completion, the reaction mixture was elutedthrough celite and the solvent was removed via rotary evaporation. Theresidue was then triturated with pentane. The resulting solid wasisolated via filtration and further dried under vacuum. See FIG. 20.

Example 11 Synthesis of N-Phenyl-2-aminobiphenylpalladium MesylatePrecatalysts

N-phenyl-[1,1′-biphenyl]-2-ammonium Mesylate:

A 50 mL round-bottomed flask equipped with a stir bar was charged with2-(N-phenyl)aminobiphenyl (1.09 g, 4.4 mmol, 1.00 eq) and diethyl ether(25 mL). Methanesulfonic acid (285 μL, 4.4 mmol, 1.00 eq) was addeddropwise and the reaction mixture was stirred for 30 minutes. Thesolvent was then removed via rotary evaporation and the product wasfurther dried under vacuum to yield the title compound as a green oil.

N-Phenyl-2-aminobiphenylpalladium Mesylate Dimer

A 24 mL screw-top tube equipped with a stir bar was charged withpalladium acetate (1.00 g, 4.48 mmol, 1.00 eq) and a solution ofN-phenyl-[1,1′-biphenyl]-2-ammonium mesylate (1.48 g, 4.48 mmol, 1.00eq) in THF (10 mL). The reaction mixture was stirred at 50° C. for 15minutes, until a yellow precipitate formed. After cooling to roomtemperature the solid was filtered and washed with diethyl ether (2×10mL) and pentane (2×10 mL) and further dried under vacuum to afford thetitle compound as a yellow solid. Yield: 1.4 g, 65%.

N-Phenyl-2-aminobiphenylpalladium Mesylate Precatalyst (RepresentativeProcedure with XPhos)

A test tube, equipped with a magnetic stir bar and fitted with a Teflonscrew-cap, was charged with N-Phenyl-2-aminobiphenylpalladium mesylatedimer (446 mg, 0.50 mmol, 0.50 eq) and XPhos (476 mg, 1.00 mmol, 1.00eq), followed by DCM (5 mL). The reaction was stirred at roomtemperature for 1 h. After completion, the reaction mixture wastransferred to a scintillation vial and the solvent was removed undervacuum at room temperature. The residue was then triturated withpentane. The resulting solid was isolated via filtration and furtherdried under vacuum to provide the title compound as a yellow solid. SeeFIG. 21.

Example 12 Synthesis of N-Methyl-2-aminobiphenylpalladium MesylatePrecatalyst

N-methyl-[1,1′-biphenyl]-2-ammonium Mesylate:

A 50-mL round-bottomed flask equipped with a stir bar was charged with2-(N-methyl)aminobiphenyl (600 mg, 3.25 mmol, 1.00 eq) and diethyl ether(25 mL). Methanesulfonic acid (212 μL, 3.25 mmol, 1.00 eq) was addeddropwise and the reaction mixture was sonicated for 30 minutes and thenstirred for 30 minutes. The resulting solid was filtered and furtherdried under vacuum to provide the title compound as a white solid.Yield: 578 mg, 61%.

N-methyl-2-aminobiphenylpalladium Mesylate Dimer

A 24-mL screw-top tube equipped with a stir bar was charged withpalladium acetate (448 mg, 2.00 mmol, 1.00 eq) and a solution ofN-methyl-[1,1′-biphenyl]-2-ammonium mesylate (578 mg, 2.00 mmol, 1.00eq) in THF (10 mL). The reaction mixture was stirred at 50° C. for 15minutes, until the solution became yellow in color. After cooling toroom temperature the solvent was removed via rotary evaporation and theresulting residue was treated with diethyl ether (25 mL) to precipitatea beige solid. The resulting solid was filtered and further dried undervacuum. Yield: 530 mg, 69%.

N-Methyl-2-aminobiphenylpalladium Mesylate Precatalyst—RepresentativeProcedure with XPhos

A test tube, equipped with a magnetic stir bar and fitted with a Teflonscrew-cap, was charged with N-methyl-2-aminobiphenylpalladium mesylatedimer (96 mg, 0.125 mmol, 0.50 eq) and XPhos (119 mg, 0.25 mmol, 1.00eq), followed by DCM (5 mL). The reaction was stirred at roomtemperature for 1 h. After completion, the reaction mixture wastransferred to a scintillation vial and the solvent was removed undervacuum at room temperature. The residue was then triturated withpentane. The resulting solid was isolated via filtration and furtherdried under vacuum to provide the title compound as an off-white solid.

INCORPORATION BY REFERENCE

All of the U.S. patents and U.S. patent application publications citedherein are hereby incorporated by reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

We claim:
 1. A precatalyst of formula III:

wherein, independently for each occurrence, X is a non-coordinatinganion; R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, orhalo; L is a trialkylphosphine, triarylphosphine, dialkylarylphosphine,alkyldiarylphosphine, bis(phosphine), phosphoramide, amine, bis(amine),or N-heterocyclic carbene; and R² is alkyl, haloalkyl or aryl.
 2. Theprecatalyst of claim 1, wherein L is selected from the group consistingof PPh₃, Ph₂P—CH₃, PhP(CH₃)₂, P(o-tol)₃, PCy₃, P(tBu)₃, BINAP, dppb,dppe, dppf, dppp,

R^(x) is alkyl, aralkyl, cycloalkyl, or aryl; X¹ is CH or N; R³ is H oralkyl; R⁴ is H, alkoxy, or alkyl; R⁵ is alkyl or aryl; and n is 1, 2, 3,or
 4. 3. The precatalyst of claim 1, wherein X is selected from thegroup consisting of boron tetrafluoride, tetraarylborates,hexafluoroantimonate, phosphorus tetrafluoride, phosphorus hexafluoride,alkylsulfonate, haloalkylsulfonate, arylsulfonate, perchlorate,bis(alkylsulfonyl)amide, bis(fluoroalkylsulfonyl)amide,bis(arylsulfonyl)amide, (fluoroalkylsulfonyl)(fluoroalkylcarbonyl)amide,nitrate, nitrite, sulfate, hydrogensulfate, alkyl sulfate, aryl sulfate,carbonate, bicarbonate, carboxylate, phosphate, hydrogen phosphate,dihydrogen phosphate, phosphinate, and hypochlorite.
 4. The precatalystof claim 1, wherein R¹ is H or alkyl.
 5. The precatalyst of claim 1,wherein R², where present, is substituted or unsubstituted alkyl.
 6. Theprecatalyst of claim 1, wherein R², where present, is substituted orunsubstituted aryl.
 7. The precatalyst of claim 1, wherein theprecatalyst is selected from the group consisting of:

wherein R is H, alkyl, or aryl; L is selected from the group consistingof PPh₃, Ph₂P—CH₃, PhP(CH₃)₂, P(o-tol)₃, PCy₃, P(tBu)₃, BINAP, dppb,dppe, dppf, dppp,

R^(x) is alkyl, aralkyl, cycloalkyl, or aryl; X¹ is CH or N; R³ is H oralkyl; R⁴ is H, alkoxy, or alkyl; R⁵ is alkyl or aryl; and n is 1, 2, 3,or
 4. 8. A dimer of:

wherein, independently for each occurrence, X is a non coordinatinganion; and R¹ is H, alkyl, haloalkyl, hydroxy, alkoxy, aryloxy, aryl, orhalo; R² is alkyl, haloalkyl or aryl.
 9. The dimer of claim 8, wherein Xis selected from the group consisting of boron tetrafluoride,tetraarylborates, hexafluoroantimonate, phosphorus tetrafluoride,phosphorus hexafluoride, alkylsulfonate, haloalkylsulfonate,arylsulfonate, perchlorate, bis(alkylsulfonyl)amide,bis(fluoroalkylsulfonyl)amide, bis(arylsulfonyl)amide,(fluoroalkylsulfonyl)(fluoroalkylcarbonyl)amide, nitrate, nitrite,sulfate, hydrogensulfate, alkyl sulfate, aryl sulfate, carbonate,bicarbonate, carboxylate, phosphate, hydrogen phosphate, dihydrogenphosphate, phosphinate, and hypochlorite.
 10. The dimer of claim 8,wherein R¹ is H or alkyl.
 11. The dimer of claim 8, wherein R², wherepresent, is substituted or unsubstituted alkyl.
 12. The dimer of claim8, wherein R², where present, is substituted aryl or unsubstituted aryl.